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"Keeble, Susan"
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Relationship continuity and understanding challenging behaviours in spouses/partners of those with an acquired brain injury
This thesis is submitted in partial fulfilment of the requirements for the degree of Doctorate in Clinical Psychology at the University of Birmingham. The thesis consists of two volumes which illustrate research (Volume I) and clinical work (Volume II). All identifying information has been anonymised to ensure confidentiality. Volume I This first volume contains three chapters. The first is a systematic review of the research literature regarding carers’ attributions of challenging behaviour in care-recipients with dementia. The second is a research study examining the association between spousal carers’ perceptions of relationship continuity, and their understanding and management of challenging behaviour, for partners with an acquired brain injury. The third is a public dissemination document providing an accessible overview of the research study. Volume II This second volume contains four clinical practice reports (CPRs) and an abstract of a fifth CPR which was presented orally. The first CPR describes the assessment and formulation of a 48-year-old man with mild learning disabilities who was experiencing anxiety and low mood, from cognitive behavioural and systemic perspectives. The second is a service evaluation of a dementia-friendly inpatient unit, identifying the barriers and facilitators to good care. The third is a single-case experimental design of a 33-year-old man in a medium-secure forensic service who experienced anxiety. The fourth describes a piece of leadership and consultation work, regarding how hospice staff cope with grief. The final CPR is an abstract of an oral presentation of a case study of a graded exposure intervention with a 16-year-old female.
Dissertation
Environmental cold exposure increases blood flow and affects pain sensitivity in the knee joints of CFA-induced arthritic mice in a TRPA1-dependent manner
Background
The effect of cold temperature on arthritis symptoms is unclear. The aim of this study was to investigate how environmental cold affects pain and blood flow in mono-arthritic mice, and examine a role for transient receptor potential ankyrin 1 (TRPA1), a ligand-gated cation channel that can act as a cold sensor.
Methods
Mono-arthritis was induced by unilateral intra-articular injection of complete Freund’s adjuvant (CFA) in CD1 mice, and in mice either lacking TRPA1 (TRPA1 KO) or respective wildtypes (WT). Two weeks later, nociception and joint blood flow were measured following exposure to 10 °C (1 h) or room temperature (RT). Primary mechanical hyperalgesia in the knee was measured by pressure application apparatus; secondary mechanical hyperalgesia by automated von Frey system; thermal hyperalgesia by Hargreaves technique, and weight bearing by the incapacitance test. Joint blood flow was recorded by full-field laser perfusion imager (FLPI) and using clearance of
99m
Technetium. Blood flow was assessed after pretreatment with antagonists of either TRPA1 (HC-030031), substance P neurokinin 1 (NK
1
) receptors (SR140333) or calcitonin gene-related peptide (CGRP) (CGRP
8–37
). TRPA1, TAC-1 and CGRP mRNA levels were examined in dorsal root ganglia, synovial membrane and patellar cartilage samples.
Results
Cold exposure caused bilateral primary mechanical hyperalgesia 2 weeks after CFA injection, in a TRPA1-dependent manner. In animals maintained at RT, clearance techniques and FLPI showed that CFA-treated joints exhibited lower blood flow than saline-treated joints. In cold-exposed animals, this reduction in blood flow disappears, and increased blood flow in the CFA-treated joint is observed using FLPI. Cold-induced increased blood flow in CFA-treated joints was blocked by HC-030031 and not observed in TRPA1 KOs. Cold exposure increased TRPA1 mRNA levels in patellar cartilage, whilst reducing it in synovial membranes from CFA-treated joints.
Conclusions
We provide evidence that environmental cold exposure enhances pain and increases blood flow in a mono-arthritis model. These changes are dependent on TRPA1. Thus, TRPA1 may act locally within the joint to influence blood flow via sensory nerves, in addition to its established nociceptive actions.
Journal Article
The role of substance P in microvascular responses in murine joint inflammation
1 Rheumatoid arthritis is a serious, inflammatory disease of the distal joints that has a possible neurogenic component underlying its pathology. 2 Substance P (SP), an endogenous neuropeptide that acts upon the neurokinin 1 (NK1) receptor, is released from sensory nerves and is involved in neurogenic inflammation. 3 In this study, we have developed novel techniques to determine the contribution of SP to microvascular responses in a model of complete Freund's adjuvant (CFA)‐induced arthritis in NK1 knockout mice. 4 Detailed analysis in normal mice revealed that CFA (20 μg i.art.)‐induced plasma extravasation was raised from 18 to 72 h, when compared with intravascular volume. By comparison, knee swelling was sustained for 3 weeks. Neutrophil accumulation mirrored plasma extravasation. SP (10 pmol i.art.) caused significant acute plasma extravasation, but not other parameters, in wild type (WT), but not NK1 knockout mice. CFA (10 μg i.art.) induced a significantly decreased intravascular volume, presumably due to decreased blood flow, at early time points (5 and 7 h) in WT but not NK1 knockouts. Otherwise, similar responses in WT and NK1 knockout mice were observed. However, injection of SP into CFA‐pretreated joints caused a significant enhancement of plasma extravasation and knee swelling in the WT but not NK1 knockouts. 5 In conclusion, the present study has used novel techniques in WT and NK1 knockout mice to show that SP can modulate vascular tone and permeability in the inflamed joint via activation of the NK1 receptor and that SP‐induced responses are more pronounced where pre‐existing inflammation is present. British Journal of Pharmacology (2005) 144, 1059–1066. doi:10.1038/sj.bjp.0706131
Journal Article
Neutrophils-derived peroxynitrite contributes to acute hyperalgesia and cell influx in zymosan arthritis
We investigated the contribution of neutrophils to joint hyperalgesia and peroxynitrite formation in zymosan arthritis. Rats received 1 mg zymosan intra-articular, and joint hyperalgesia was measured using the rat knee-joint articular incapacitation test. After 6 h, joint exudates were collected by aspiration for the assessment of cell influx, myeloperoxidase activity, and nitrite (as an index of nitric oxide formation) levels. Nitrotyrosine content, used as an index of peroxynitrite formation, was measured in joint exudates, using enzyme-linked immunosorbent assay. A group of rats was rendered neutropenic through the administration of a rabbit anti-rat neutrophil antibody (2 ml kg(-1), i.p.) 30 min before injection of 1 mg zymosan intra-articular. Other groups received uric acid (100 or 250 mg kg(-1), i.p.), the peroxynitrite scavenger, 30 min before 1 mg zymosan intra-articular. Controls received the vehicle. The significant inhibition of joint hyperalgesia in neutropenic animals was associated to significantly decreased cell influx, myeloperoxidase activity, nitric oxide, and nitrotyrosine levels in the joint exudates, as compared to naive rats. Uric acid administration inhibited both hyperalgesia and cell influx, as compared to controls. Neutrophils are involved in both nitric oxide and peroxynitrite formation in zymosan arthritis, thereby contributing to acute joint hyperalgesia. Scavenging of reactive nitrogen species (e.g. peroxynitrite) inhibits neutrophil migration and joint hyperalgesia in the acute phase of zymosan arthritis in rats.
Journal Article
Reactive nitrogen species scavenging, rather than nitric oxide inhibition, protects from articular cartilage damage in rat zymosan‐induced arthritis
The contribution of nitric oxide (NO) and peroxynitrite (PN) to inflammation in a zymosan‐induced (1 mg, intra‐articular, i.art.) rat model of arthritis was assessed by histopathology and by measuring the glycosaminoglycan (GAG) content of the articular cartilage. Progression of the chronic synovitis in zymosan‐induced arthritis (ZYA) was associated with increased nitrite and nitrotyrosine (3‐NT) levels in the joint exudates that paralleled a progressive loss of the GAG content. An increase in 3‐NT was also observed after i.art. PN. The nonselective nitric oxide synthase (NOS) inhibitor L‐NG‐nitroarginine methyl ester (25–75 mg kg−1day−1) or the selective inducible NOS inhibitor aminoguanidine (50–100 mg kg−1day−1) given 1 h before (prophylactic) or 3 days after (therapeutic) injection of the zymosan ameliorated the synovitis, but worsened the GAG loss, as measured at the end of the experiment (day 7). The PN scavenger uric acid (100–250 mg kg−1 i.p. four times daily) given prophylactically until the end of the experiment (day 14), in a dose compatible with its PN scavenging activity, significantly decreased both the synovitis and the GAG loss. In conclusion, PN formation is associated with cartilage damage in addition to proinflammatory activity in ZYA. NOS inhibitors and a PN scavenger were able to reduce the cellular infiltration, while displaying opposite effects on cartilage homeostasis either by enhancing or ameliorating the damage, respectively. British Journal of Pharmacology (2004) 141, 172–182. doi:10.1038/sj.bjp.0705600
Journal Article
Novel inactivating mutations of FANCC in Brazilian patients with Fanconi anemia
We have identified three novel FANCC mutations, a truncating single base insertion in exon 4 (c.455_456dupA), a point mutation in exon 13 (c.1390C>T), and a splice site mutation leading to deletion of exon 9, in two Brazilian FA‐C patients, each a compound heterozygote. Using complementation analyses, we confirmed that two of these mutations inactivate the function of the FANCC protein. Published 2006 Wiley‐Liss, Inc.
Journal Article